Two principal ways have been used to obtain the enantiomerically pure S-form of the amine of the formula I and R-form of the amine of the formula I, i.e. resolution of racemic amine of the formula I and stereocontrolled synthesis of the optically active amine of the formula I from a chiral starting material. The resolution procedures are described in GB 1 207 752 and AU 526 077 but they involve substantial loss of material and the requirement of often expensive resolving agents. The most attractive procedures rely upon the stereocontrolled conversion of a suitable chiral compound.
Stereocontrolled syntheses have been disclosed by Synthelabo in GB 1 555 890 and by Ravizza in GB 2 014 990.
The procedures of Synthelabo start with the S-form or R-form of proline (Scheme 1), S-form or R-form of glutamic acid or S-form or R-form of prolinol. The procedures cover compounds of the formula I with different R.sup.a -groups such as alkyl, cycloalkyl and substituted phenyl. The preferred method using the S-form or the R-form of proline as starting material is a four step synthesis consisting of esterification, aminolysis, acylation and reduction as outlined in Scheme 1. No yields or optical purities besides optical rotations are disclosed. ##STR3##
The procedure starting from the S-form or R-form of glutamic acid is a six step synthesis involving condensation, hydrogenation, cyclization, esterification, aminolysis and reduction. No yields are reported.
The Ravizza patent describes a method of preparing the (S)-2-amino-methyl-1-ethyl-pyrrolidine (the compound of the formula I wherein R.sup.1 =CH.sub.3) in four steps involving acetylation, reduction, chlorination and amination as outlined in Scheme 2. The crude amine obtained in ca 35% yield from proline is not characterized but converted to sulpiride and purified as such. ##STR4##
N-alkylation of L-proline with retention of the stereochemistry is described in Beilstein, E III/IV 22, Syst. No. 3244, p. 23-24.
The denoted compounds in the reaction schemes are described in the above-mentioned prior art citations.
1-methyl-2-pyrrolidinecarboxamide prepared from L-proline is described in the European Patent Application 0121244. In Arch. Pharm. 309 (5), p. 380-85 (1976) is described the preparation of methyl(-)-1-methyl-2-pyrrolidinecarboxylate from (-)-proline by N-alkylation followed by O-alkylation. Arch. Pharm 316 (9), p. 771-81 (1983) indicates manufacture of a 1 -substituted phenyl methyl -2-pyrrolidinecarboxylate from methyl L-proline by N-alkylation.